The present invention relates to oxygen-containing heterocyclic compounds which exhibit phosphodiesterase (PDE) IV inhibitory activity and which are useful as therapeutic agents for inflammatory allergic diseases such as bronchial asthma, allergic rhinitis, and nephritis; autoimmune diseases such as rheumatoid arthritis, multiple sclerosis, Crohn""s disease, psoriasis, and systemic lupus erythematosus; diseases of the central nervous system such as depression, amnesia, and dementia; organopathy associated with ischemic reflux caused by cardiac failure, shock, and cerebrovascular diseases, and the like; insulin-resistant diabetes; wounds; AIDS, and the like.
Heretofore, it is known that the functions of numerous hormones and neurotransmitters are expressed by an increase in the concentration of adenosine 3xe2x80x2,5xe2x80x2-cyclic monophosphate (cAMP) or guanosine 3xe2x80x2,5xe2x80x2-cyclic monophosphate (cGMP), both of which are the secondary messengers in cells. The cellular concentrations of cAMP and cGMP are controlled by the generation and decomposition thereof, and their decomposition is carried out by PDE. Therefore, when PDE is inhibited, the concentrations of these secondary cellular messengers increase. Up to the present, 7 kinds of PDE isozymes have been found, and the isozyme-selective PDE inhibitors are expected to exhibit pharmacological effect based on their physiological significance and distribution in vivo (TiPS, 1990, 11, 150, TiPS, 1991, 12, 19).
It is known that the activation of inflammatory leukocytes can be suppressed by increasing the concentration of the cellular cAMP. The activation of leukocytes causes secretion of inflammatory cytokines such as tumor necrosis factor (TNF), and expression of the cellular adhesion molecules such as intercellular adhesion molecules (ICAM), followed by cellular infiltration [J. Mol. Cell. Cardiol., 1989, 12, (Suppl. II), S61].
It is known that the contraction of a respiratory smooth muscle can be suppressed by increasing the concentration of the cellular cAMP (T. J. Torphy in Directions for New Anti-Asthma Drugs, eds S. R. O""Donell and C. G. A. Persson, 1988, 37, Birkhauser-Verlag). The contraction of a respiratory smooth muscle is a main symptom of bronchial asthma. Inflammatory-leukocyte infiltration of neutrophils and the like is observed in lesions of organopathy associated with ischemic reflux such as myocardial ischemia. It has been found that the IV type PDE (PDE IV) mainly participates in the decomposition of cAMP in these inflammatory cells and tracheal smooth muscle cells. Therefore, the inhibitors selective for PDE IV are expected to have therapeutic and/or preventive effect on inflammatory diseases, respiratory obstructive diseases, and ischemic diseases.
Further, the PDE IV inhibitors are expected to prevent the progress and spread of the inflammatory reaction transmitted by inflammatory cytokines such as TNFa and interleukin (IL)-8xcex1, because the PDE IV inhibitors suppress the secretion of these cytokines by increasing the concentration of cAMP. For example, TNFxcex1 is reported to be a factor of insulin-resistant diabetes because it declines the phosphorylating mechanism of insulin receptors of muscle and fat cells (J. Clin. Invest., 1994, 94, 1543-1549). Similarly, it is suggested that TNFxcex1 participates in the onset and progress of autoimmune diseases such as rheumatoid arthritis, multiple sclerosis, and Crohn""s disease, and that the PDE IV inhibitors are useful for these diseases (Nature Medicine, 1995, 1, 211-214 and 244-248).
Drugs which increase cAMP are reported to enhance the healing of wounds [Nippon Yakuri-gakkai, the 68th annual meeting (Nagoya), P3-116, 1995].
PDE IV-selective inhibitors having catechol structures are disclosed in WO96-00218, WO96-00215, WO95-35285, WO95-35284, WO95-35283, WO95-35281, WO95-28926, WO95-27692, WO95-24381, WO95-22520, WO95-20578, WO95-17399, WO95-17392, WO95-14681, WO95-14680, WO95-14667, WO95-09837, WO95-09836, WO95-09627, WO95-09624, WO95-09623, WO95-08534, WO95-04046, WO95-04045, WO95-03794, WO95-01338, WO95-00516, WO95-00139, U.S. Pat. No. 5,461,056, EP0685479, EP0685475, EP0685474, EP0671389, WO93-25517, WO94-25437, EP623607, WO94-20446, WO94-20455, WO94-14800, WO94-14742, WO94-12461, WO94-10118, WO94-02465, WO93-19751, WO93-19750, WO93-19749, WO93-19748, WO93-19747, WO93-18024, WO93-15048, WO93-07141, Japanese Published Unexamined Patent Application No. 117239/93, WO92-19594, and EP497564.
Further compounds which have a benzofuran structure and PDE IV-inhibitory activity are reported (Bioorganic Med. Chem. Lett., 1994, 14, 1855-1860, EP685479, WO96-03399).
Heretofore, benzofuran derivatives are industrially useful and are disclosed in patents of intermediates of product materials, light emitting elements, agricultural chemicals, anthelminthics, drugs, and the like.
Benzofuran, benzopyran, and benzodioxole derivatives which have a carboxyl group or a tetrazolyl group are disclosed in J. Med. Chem., 1988, 31, 84-91, and Japanese Published Unexamined Patent Application Nos. 50977/86, 126061/86, 143371/86, and 230760/87, and are described to exhibit leukotriene antagonism, phospholipase inhibitory activity, 5xcex1 reductase inhibitory activity, aldose-reductase inhibitory activity, and the like.
WO92-01681 and WO92-12144 disclose benzofuran and benzopyran derivatives which exhibit acyl-CoA acetyltransferase (ACAT) inhibitory activity.
WO93-01169 discloses benzofuran derivatives which exhibit tachykinin antagonism.
EP307172 and U.S. Pat. No. 4,910,193 disclose benzofuran derivatives which exhibit antagonistic activity against serotonin (5HT)3 receptors.
The present invention relates to oxygen-containing heterocyclic compounds represented by following Formula (I): 
wherein R1 and R2 independently represent hydrogen, substituted or unsubstituted lower alkyl, cycloalkyl, polycycloalkyl, lower alkenyl, cycloalkenyl, substituted or unsubstituted aryl, a substituted or unsubstituted aromatic heterocyclic group, aralkyl, cyano, or xe2x80x94(CH2)nxe2x80x94E1xe2x80x94COxe2x80x94G[wherein E1 represents a bond, O, or NH; and G1 represents hydrogen, substituted or unsubstituted lower alkyl, cycloalkyl, polycycloalkyl, substituted or unsubstituted aryl, a substituted or unsubstituted aromatic heterocyclic group, aralkyl, OR6 (wherein R6 represents hydrogen, lower alkyl, cycloalkyl, polycycloalkyl, substituted or unsubstituted aryl, a substituted or unsubstituted aromatic heterocyclic group, or aralkyl), or NR7R8 (wherein R7 represents hydrogen, substituted or unsubstituted lower alkyl, cycloalkyl, polycycloalkyl, substituted or unsubstituted aryl, a substituted or unsubstituted aromatic heterocyclic group, substituted or unsubstituted aralkyl, or substituted or unsubstituted heteroarylalkyl; and R8 represents substituted or unsubstituted lower alkyl, cycloalkyl, polycycloalkyl, substituted or unsubstituted aryl, a substituted or unsubstituted aromatic heterocyclic group, substituted or unsubstituted aralkyl, or substituted or unsubstituted heteroarylalkyl; or R7 and R8 are combined to represent a substituted or unsubstituted heterocyclic group containing at least one nitrogen atom); and n represents an integer of 0 to 4]; R1 and R2 are combined to represent a saturated carbon ring together with a carbon atom adjacent thereto; or R2, and R11 or R13 described below are combined to form a single bond; R3 represents hydrogen, phenyl, or halogen; R4 represents hydroxy or substituted or unsubstituted lower alkoxy; A represents xe2x80x94C(R9)(R10)xe2x80x94 (wherein R9 and R10 independently represent hydrogen, substituted or unsubstituted lower alkyl, cycloalkyl, or polycycloalkyl) or O; B represents O, NR11 [wherein R11 represents hydrogen, lower alkyl, cycloalkyl, polycycloalkyl, lower alkenyl, cycloalkenyl, substituted or unsubstituted aryl, a substituted or unsubstituted aromatic heterocyclic group, aralkyl, or xe2x80x94(CH2)mxe2x80x94E2xe2x80x94COxe2x80x94G2 (wherein E2, G2, and m have the same meanings as the above-described E1, G1, and n, respectively); or R11 and R2 are combined to form a single bond], xe2x80x94C (R12)(R13)xe2x80x94 or xe2x80x94C(R12)(R13)xe2x80x94Oxe2x80x94 [wherein R12 and R13 independently represent hydrogen, substituted or unsubstituted lower alkyl, hydroxy, substituted or unsubstituted lower alkoxy, lower alkanoyloxy, substituted or unsubstituted lower alkanoyl, substituted or unsubstituted cycloalkylcarbonyl, lower alkoxycarbonyl, cycloalkyl, polycycloalkyl, lower alkenyl, cycloalkenyl, substituted or unsubstituted aryl, a substituted or unsubstituted aromatic heterocyclic group, substituted or unsubstituted aralkyl, halogen, cyano, or xe2x80x94(CH2)pxe2x80x94E3xe2x80x94COxe2x80x94G3 (wherein E3, G3, and p have the same meanings as the above-described E1, G1, and n, respectively); R13 and R2 are combined to form a single bond; or R13 and R2 are combined to form a saturated carbon ring together with two carbon atoms adjacent thereto];
xe2x80x94C(R14)(R15)xe2x80x94C(R16)(R17)xe2x80x94 or xe2x80x94C(R14)(R15)xe2x80x94C(R16)(R17)xe2x80x94Oxe2x80x94
[wherein R14 and R15 independently represent hydrogen, substituted or unsubstituted lower alkyl, hydroxy, substituted or unsubstituted lower alkoxy, lower alkanoyloxy, substituted or unsubstituted lower alkanoyl, substituted or unsubstituted cycloalkylcarbonyl, lower alkoxycarbonyl, cycloalkyl, polycycloalkyl, lower alkenyl, cycloalkenyl, substituted or unsubstituted aryl, a substituted or unsubstituted aromatic heterocyclic group, substituted or unsubstituted aralkyl, halogen, or cyano; or R14 and R15 are combined to form O; and R16 and R17 independently represent hydrogen, substituted or unsubstituted lower alkyl, hydroxy, substituted or unsubstituted lower alkoxy, lower alkanoyloxy, substituted or unsubstituted lower alkanoyl, substituted or unsubstituted cycloalkylcarbonyl, lower alkoxycarbonyl, cycloalkyl, polycycloalkyl, lower alkenyl, cycloalkenyl, substituted or unsubstituted aryl, a substituted or unsubstituted aromatic heterocyclic group, substituted or unsubstituted aralkyl, halogen, or cyano; R17 and R15 are combined to form a single bond; or R17 and R15 are combined to form a saturated carbon ring together with two carbon atoms adjacent thereto]; or xe2x80x94C(R12xe2x80x2)(R13xe2x80x2)xe2x80x94C(R14xe2x80x2)(R15xe2x80x2)xe2x80x94C(R16xe2x80x2)(R17xe2x80x2) or xe2x80x94C(R12xe2x80x2)(R13xe2x80x2)xe2x80x94C(R14xe2x80x2)(R15xe2x80x2)xe2x80x94C(R16xe2x80x2)(R17xe2x80x2)xe2x80x94Oxe2x80x94 [wherein R12xe2x80x2 and R13xe2x80x2 independently represent hydrogen, substituted or unsubstituted lower alkyl, hydroxy, substituted or unsubstituted lower alkoxy, lower alkanoyloxy, substituted or unsubstituted lower alkanoyl, substituted or unsubstituted cycloalkylcarbonyl, lower alkoxycarbonyl, cycloalkyl, polycycloalkyl, lower alkenyl, cycloalkenyl, substituted or unsubstituted aryl, a substituted or unsubstituted aromatic heterocyclic group, substituted or unsubstituted aralkyl, halogen, or cyano; or R12xe2x80x2 and R13xe2x80x2 are combined to form O; R14xe2x80x2 and R15xe2x80x2 independently represent hydrogen, substituted or unsubstituted lower alkyl, hydroxy, substituted or unsubstituted lower alkoxy, lower alkanoyloxy, substituted or unsubstituted lower alkanoyl, substituted or unsubstituted cycloalkylcarbonyl, lower alkoxycarbonyl, cycloalkyl, polycycloalkyl, lower alkenyl, cycloalkenyl, substituted or unsubstituted aryl, a substituted or unsubstituted aromatic heterocyclic group, substituted or unsubstituted aralkyl, halogen, or cyano; R13xe2x80x2 and R15xe2x80x2 are combined to form a single bond; or R13xe2x80x2 and R15xe2x80x2 form a saturated carbon ring together with two adjacent carbon atoms; and R16xe2x80x2 and R17xe2x80x2 independently represent hydrogen, substituted or unsubstituted lower alkyl, hydroxy, substituted or unsubstituted lower alkoxy, lower alkanoyloxy, substituted or unsubstituted lower alkanoyl, substituted or unsubstituted cycloalkylcarbonyl, lower alkoxycarbonyl, cycloalkyl, polycycloalkyl, lower alkenyl, cycloalkenyl, substituted or unsubstituted aryl, a substituted or unsubstituted aromatic heterocyclic group, substituted or unsubstituted aralkyl, halogen, or cyano; R15xe2x80x2 and R17xe2x80x2 are combined to form a single bond; or R15xe2x80x2 and R17xe2x80x2 form a saturated carbon ring together with two adjacent carbon atoms]. D represents (i) xe2x80x94C(R18)(R19)xe2x80x94Xxe2x80x94 [wherein R18 represents hydrogen, substituted or unsubstituted lower alkyl, cycloalkyl, polycycloalkyl, lower alkenyl, cycloalkenyl, substituted or unsubstituted aryl, a substituted or unsubstituted aromatic heterocyclic group, hydroxy, substituted or unsubstituted lower alkoxy, or lower alkanoyloxy; and R19 represents hydrogen, substituted or unsubstituted lower alkyl, cycloalkyl, polycycloalkyl, lower alkenyl, cycloalkenyl, substituted or unsubstituted aryl, a substituted or unsubstituted aromatic heterocyclic group, hydroxy, substituted or unsubstituted lower alkoxy, lower alkanoyloxy, lower alkanoyl, cycloalkylcarbonyl, lower alkoxycarbonyl, or cyano; or R18 and R19 are combined to form O, S, or NR20 (wherein R20 represents hydrogen, substituted or unsubstituted lower alkyl, cycloalkyl, polycycloalkyl, lower alkenyl, cycloalkenyl, substituted or unsubstituted aryl, a substituted or unsubstituted aromatic heterocyclic group, hydroxy, substituted or unsubstituted lower alkoxy, or lower alkanoyloxy); X represents xe2x80x94C(R21)(R22)xe2x80x94 (wherein R21 and R22 independently represent hydrogen, substituted or unsubstituted lower alkyl, cycloalkyl, polycycloalkyl, lower alkenyl, cycloalkenyl, substituted or unsubstituted aryl, a substituted or unsubstituted aromatic heterocyclic group, lower alkanoyl, cycloalkylcarbonyl, lower alkoxycarbonyl, or cyano) or S; or X represents NR23 (wherein R23 represents hydrogen, substituted or unsubstituted lower alkyl, cycloalkyl, substituted or unsubstituted aryl, a substituted or unsubstituted aromatic heterocyclic group, or substituted or unsubstituted aralkyl, or R23 and R5 are combined to form a substituted or unsubstituted heterocyclic group containing at least one nitrogen atom) unless R1 and R2 simultaneously represent substituted or unsubstituted lower alkyl, cycloalkyl, polycycloalkyl, lower alkenyl, or cycloalkenyl included in the above definition, A represents oxygen, and B represents CH2], (ii) xe2x80x94C(R19a)xe2x95x90Yxe2x80x94 [wherein R19a represents hydrogen, substituted or unsubstituted lower alkyl, cycloalkyl, polycycloalkyl, lower alkenyl, cycloalkenyl, substituted or unsubstituted aryl, a substituted or unsubstituted aromatic heterocyclic group, hydroxy, substituted or unsubstituted lower alkoxy, lower alkanoyloxy, lower alkanoyl, cycloalkylcarbonyl, lower alkoxycarbonyl, or cyano; and Y represents xe2x80x94C(R24)xe2x80x94Zxe2x80x94 (wherein R24 represents hydrogen, substituted or unsubstituted lower alkyl, cycloalkyl, polycycloalkyl, lower alkenyl, cycloalkenyl, substituted or unsubstituted aryl, a substituted or unsubstituted aromatic heterocyclic group, lower alkanoyl, cycloalkylcarbonyl, lower alkoxycarbonyl, or cyano; or R24 and R19a are combined to form a single bond; and Z represents CONH, CONHCH2, or a bond) or N], or (iii) a bond; and R5 represents hydrogen, substituted or unsubstituted lower alkyl, substituted or unsubstituted aralkyl, substituted or unsubstituted aryl, a substituted or unsubstituted aromatic heterocyclic group, cycloalkyl, pyridine-N-oxide, cyano, or lower alkoxycarbonyl, or R5 and R23 are combined to form a substituted or unsubstituted heterocyclic group containing at least one nitrogen atom; or pharmaceutically acceptable salts thereof.
Hereinafter, the compounds represented by Formula (I) are referred to as Compounds (I). The same applies to the compounds of other formula numbers.
In the definitions of the groups in Formula (I), the lower alkyl and the lower alkyl moiety of the lower alkoxy, the lower alkanoyloxy, the lower alkanoyl, the lower alkoxycarbonyl, and the heteroarylalkyl include straight-chain or branched alkyl groups having 1 to 8 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, heptyl, and octyl; the cycloalkyl and the cycloalkyl moiety of the cycloalkylcarbonyl include cycloalkyl groups having 3 to 10 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, and cyclodecyl; and the polycycloalkyl includes polycycloalkyl groups having 4 to 12 carbon atoms, such as bicyclo[3.2.1]octyl, bicyclo[4.3.2]undecyl, adamantyl, and noradamantyl. The lower alkenyl includes straight-chain or branched alkenyl groups having 2 to 8 carbon atoms, such as vinyl, 1-propenyl, allyl, methacryl, 1-butenyl, crotyl, pentenyl, isoprenyl, hexenyl, heptenyl, and octenyl; and the cycloalkenyl includes cycloalkenyl groups having 4 to 10 carbon atoms, such as cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, cyclononenyl, and cyclodecenyl. The aryl includes phenyl and naphthyl; and the aralkyl includes aralkyl groups having 7 to 15 carbon atoms, such as benzyl, phenethyl, benzhydryl, and naphthylmethyl. The aromatic heterocyclic group and the heteroaryl moiety of the heteroarylalkyl include pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinolinyl, isoquinolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, thienyl, furyl, thiazolyl, oxazolyl, indolyl, indazolyl, benzimidazolyl, benzotriazolyl, and purinyl. The heterocyclic group containing at least one nitrogen atom includes pyrrolidinyl, piperidino, piperazinyl, morpholino, thiomorpholino, homopiperidino, homopiperazinyl, tetrahydropyridinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, pyrrolinyl, indolinyl, benzimidazolin-2-on-1-yl, imidazolin-2-on-1-yl, piperazin-2-on-4-yl, piperazine-2,3-dion-1-yl, piperazine-2,5-dion-1-yl, and imidazolidyl; and the saturated carbon ring together with two adjacent carbon atoms includes groups having 3 to 10 carbon atoms, such as cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclooctane, cyclononane, and cyclodecane. The halogen includes a fluorine, chlorine, bromine, and iodine atom.
The substituted lower alkyl has the same or different 1 to 2 substituents such as hydroxy, cycloalkyl, which has the same meaning as defined above, a substituted or unsubstituted aromatic heterocyclic group containing at least one nitrogen atom, and a substituted or unsubstituted heterocyclic group containing at least one nitrogen atom.
The substituted aryl, substituted aromatic heterocyclic group, and substituted aralkyl each has the same or different 1 to 3 substituents such as lower alkyl, hydroxy, lower alkoxy, lower alkanoyl, lower alkoxycarbonyl, carboxyl, aminocarbonyl, trifluoromethyl, amino, cyano, nitro, and halogen. The lower alkyl, lower alkoxy, lower alkanoyl, lower alkoxycarbonyl, and halogen each has the same meaning as defined above.
The substituted heterocyclic group containing at least one nitrogen atom has the same or different 1 to 3 substituents such as substituted or unsubstituted lower alkyl, cycloalkyl, aryl, and aralkyl. However, substituted or unsubstituted lower alkyl here has 1 to 3 substituents such as hydroxy and lower alkoxy. The lower alkyl, cycloalkyl, aryl, alkoxy, and aralkyl each has the same meaning as defined above.
The substituted aromatic heterocyclic group containing at least one nitrogen atom has the same or different 1 to 3 substituents such as substituted or unsubstituted lower alkyl, cycloalkyl, aryl, and aralkyl. However, substituted or unsubstituted lower alkyl here has 1 to 3 substituents such as hydroxy and lower alkoxy. The lower alkyl, cycloalkyl, aryl, alkoxy, and aralkyl each has the same meaning as defined above.
The substituted lower alkoxy has the same or different 1 to 3 substituents such as halogen, which has the same meaning as defined above.
The pharmaceutically acceptable salts of Compounds (I) include pharmaceutically acceptable acid addition salts, metal salts, ammonium salts, and organic amine addition salts.
The pharmaceutically acceptable acid addition salts of Compounds (I) include inorganic acid addition salts such as hydrochloride, sulfate, nitrate, and phosphate, and organic acid addition salts such as acetate, maleate, fumarate, and citrate; the pharmaceutically acceptable metal salts include alkali metal salts such as sodium salt and potassium salt, alkaline earth metal salts such as magnesium salt and calcium salt, aluminium salt; and zinc salt; the pharmaceutically acceptable ammonium salts include ammonium and tetramethylammonium; and the pharmaceutically acceptable organic amine addition salts include addition salts with morpholine and piperidine.
Processes for preparing Compound (I) are described below.
Manufacturing method 1:
Compound (Ia), which is Compound (I) in which D is (i) xe2x80x94C(R18)(R19)xe2x80x94Xxe2x80x94 and R5 is substituted or unsubstituted aryl or a substituted or unsubstituted aromatic heterocyclic group, can be obtained according to the following Processes 1-1 to 1-13.
Process 1-1:
Compound (Iaa), which is Compound (Ia) in which X is xe2x80x94C(R21)(R22)xe2x80x94, and R18 and R19 are not combined to form O, S, or NR20, can be prepared according to the following reaction steps: 
(In the formulae, R5a is substituted or unsubstituted aryl or a substituted or unsubstituted aromatic heterocyclic group in the definition of R5; R18a is a group other than hydrogen, hydroxy, substituted or unsubstituted lower alkoxy, and lower alkanoyloxy in the definition of R18, and R18a and R19 are not combined to form O, S, or NR20; R25 is substituted or unsubstituted lower alkyl or lower alkanoyl; and A, B, R1, R2, R3, R4, R19a, R21, and R22 each has the same meaning as defined above.)
The substituted or unsubstituted lower alkyl and lower alkanoyloxy in the definition of R25 each has the same meaning as defined above.
The starting Compound (II) Can be obtained according to the known methods (J. Org. Chem., 1987, 52, 4072, Org. Prep. Proced. Int., 1989, 21, 763, Synthesis, 1978, 886, Arzneim.-Forsch., 1971, 21, 204, WO93/18024, WO94/12461) or the methods described in Reference Examples. In addition, the starting Compound (III) is commercially available, or, if the starting Compound (III) is a picoline derivative, it can be obtained according to a known method (WO94/20455) or a similar method thereto.
Compound (Iaa-a), which is Compound (Iaa) in which R18 is hydroxy, can be obtained by treating Compound (III) with a base in an inert solvent at the temperature between xe2x88x92100xc2x0 C. and room temperature for 5 minutes to 10 hours, followed by reaction with a starting Compound (II) at the temperature between xe2x88x92100xc2x0 C. and the boiling point of the employed solvent for 5 minutes to 30 hours.
Examples of the base are sodium hydroxide, potassium hydroxide, sodium methoxide, potassium ethoxide, sodium hydride, potassium hydride, butyl lithium, lithium dilsopropylamide (LDA), potassium tert-butoxide, triethylamine, diisopropylethylamine, tributylamine, dicyclohexylmethylamine, N-methylmorphorine, N-methylpiperidine, diazabicycloundecene (DBU), and diazabicyclononene (DBN).
Examples of inert solvent are tetrahydrofuran (THF), dioxane, diethyl ether, ethylene glycol, triethylene glycol, glyme, diglyme, methanol, ethanol, butanol, isopropanol, dichloromethane, chloroform, benzene, toluene, dimethylformamide (DMF), and dimethyl sulfoxide (DMSO).
Compound (Iaa-b), which is Compound (Iaa) in which R18 is hydrogen, can be obtained by treating Compound (Iaa-a) with a reducing agent in the presence or absence of a catalytic amount to a largely excess amount of an acid catalyst in an inert solvent at the temperature between xe2x88x92100xc2x0 C. and the boiling point of the employed solvent for 5 minutes to 48 hours.
Examples of the acid catalyst are p-toluene-sulfonic acid, methanesulfonic acid, hydrochloric acid, trifluoroacetic acid, boron trifluoride, aluminium chloride, stannic chloride, titanium tetrachloride, zinc chloride, and ferric chloride.
Examples of the reducing agent are triethylsilane, tributylsilane, dimethylphenylsilane, and trichlorosilane.
Examples of the inert solvent are THF, dioxane, diethyl ether, ethylene glycol, triethylene glycol, glyme, diglyme, dichloromethane, chloroform, benzene, and toluene.
Compound (Iaa-ba), which is Compound (Iaa-b) in which R22 is hydrogen, can also be obtained by treating a corresponding Compound (Iba) prepared by the method described below (Process 2-2) with a reducing agent in an inert solvent at the temperature between xe2x88x92100xc2x0 C. and the boiling point of the employed solvent for 5 minutes to 30 hours, or by subjecting Compound (Iba) to hydrogenation in the presence of a catalyst in an inert solvent at the temperature between room temperature and the boiling point of the employed solvent for 5 minutes to 30 hours. An example of the reducing agent is sodium borohydride; examples of the catalyst for the hydrogenation are palladium/carbon, palladium, platinum dioxide, and Raney nickel; and examples of the inert solvent are THF, dioxane, metanol, ethanol, butanol, and isopropanol.
Compound (Iaa-c), which is Compound (Iaa) in which R18 is a group other than hydrogen, hydroxy, substituted or unsubstituted lower alkoxy, and lower alkanoyloxy in the definition of R18, and R18 and R19 are not combined to form O, S, or NR20, can be obtained by reacting Compound (Iaa-a) with an alkylating (arylating) agent in the presence of an acid catalyst in an inert solvent at the temperature between xe2x88x92100xc2x0 C. and the boiling point of the employed solvent for 5 minutes to 30 hours.
Examples of the alkylating (arylating) agent are various kinds of alkyl- or arylmagnesium bromides, alkyl- or arylmagnesium chlorides, alkyl- or arylmagnesium iodides, trialkylaluminium, tetraalkyltitanium, dialkyltitanium chloride, Tebbe reagent, and trialkylsilylnitrile.
Examples of the acid catalyst are boron trifluoride, aluminium chloride, stannic chloride, titanium tetrachloride, zinc chloride, and ferric chloride.
Examples of the inert solvent are THF, dioxane, diethyl ether, glyme, diglyme, dichloromethane, chloroform, benzene, and toluene.
Compound (Iaa-d), which is Compound (Iaa) in which R18 is substituted or unsubstituted lower alkoxy or lower alkanoyloxy, can be obtained by reacting Compound (Iaa-a) with Compound (IV) in the presence of an acid catalyst in an inert solvent or without a solvent at the temperature between xe2x88x92100xc2x0 C. and the boiling point of the employed solvent for 5 minutes to 48 hours.
Examples of the acid catalyst are p-toluene-sulfonic acid, methanesulfonic acid, hydrochloric acid, sulfuric acid, and trifluoroacetic acid.
Examples of the inert solvent are THF, dioxane, diethyl ether, glyme, diglyme, dichloromethane, chloroform, benzene, toluene, DMF, and DMSO.
Process 1-2:
Compound (Iab), which is Compound (Ia) in which X is S, and R18 and R19 are not combined to form O, S, or NR20, can be prepared by the following reaction steps: 
(In the formulae, R18b is a group other than hydroxy, substituted or unsubstituted lower alkoxy, and lower alkanoyloxy in the definition of R18, and R18b and R19 are not combined to form O, S, or NR20; and A, B, R1, R2, R3, R4, R5a, and R19a each has the same meaning as defined above.)
Compound (Va), which is Compound (V) in which R18b is hydrogen, can be obtained by treating Compound (II) with a reducing agent in an inert solvent at the temperature between xe2x88x92100xc2x0 C. and the boiling point of the employed solvent for 5 minutes to 30 hours.
Examples of the reducing agent are lithium aluminium hydride and sodium borohydride.
Examples of the inert solvent are THF, dioxane, diethyl ether, ethylene glycol, triethylene glycol, glyme, diglyme, methanol, ethanol, butanol, isopropanol, dichloromethane, chloroform, benzene, and toluene.
Compound (Vb), which is Compound (V) in which R18b is a group other than hydrogen in the definition of R18b, can be obtained by reacting Compound (II) with an alkylating (arylating) agent in an inert solvent at the temperature between xe2x88x92100xc2x0 C. and the boiling point of the employed solvent for 5 minutes to 30 hours.
Examples of the alkylating (arylating) agent are various kinds of alkyl- or arylmagnesium bromides, alkyl- or arylmagnesium chlorides, alkyl- or arylmagnesium iodides, and various kinds of alkyl or aryl lithiums.
Examples of the inert solvent are THF, dioxane, diethyl ether, glyme, diglyme, methanol, ethanol, butanol, isopropanol, dichloromethane, chloroform, benzene, and toluene.
Compound (Iab) can be obtained by reacting Compound (V) with, for example, alkyl- or arylsulfonyl chloride, in the presence of a base in an inert solvent at the temperature between xe2x88x9220xc2x0 C. and 0xc2x0 C. for 5 minutes to 5 hours, followed by reaction with Compound (VI) at the temperature between 0xc2x0 C. and the boiling point of the employed solvent for 5 minutes to 48 hours.
Examples of the base are sodium hydride, potassium hydride, butyl lithium, LDA, potassium tert-butoxide, triethylamine, diisopropylethylamine, tributylamine, dicyclohexylmethylamine, N-methylmorphorine, N-methylpiperidine, DBU, and DBN.
Examples of the alkyl- or arylsulfonyl chloride are methanesulfonyl chloride, benzenesulfonyl chloride, and p-toluenesulfonyl chloride.
Examples of the inert solvent are THF, dioxane, diethyl ether, glyme, diglyme, dichloromethane, chloroform, benzene, toluene, DMF, and DMSO.
Alternatively, Compound (Iab) can also be obtained by reacting Compound (V) with Compound (VI) in the presence of an acid catalyst in an inert solvent at the temperature between xe2x88x92100xc2x0 C. and the boiling point of the employed solvent for 5 minutes to 48 hours.
Examples of the acid catalyst are p-toluene-sulfonic acid, methanesulfonic acid, hydrochloric acid, trifluoroacetic acid, boron trifluoride, aluminium chloride, stannic chloride, titanium tetrachloride, zinc chloride, and ferric chloride.
Examples of the inert solvent are THF, dioxane, diethyl ether, glyme, diglyme, dichloromethane, chloroform, benzene, and toluene.
Process 1-3:
Compound (Iac), which is Compound (Ia) in which X is NR23, and R18 and R19 are not combined to form O, S, or NR20, can be prepared by the following reaction step: 
(In the formulae, A, B, R1, R2, R3, R4, R5a, R18b, R19a, and R23 each has the same meaning as defined above.)
Compound (Iac) can be obtained according to the method described in Process 1-2 in which Compound (Iab) is obtained from Compound (V) and Compound (VI), using Compound (VII) instead of Compound (VI).
Process 1-4:
Compound (Iad), which is Compound (Ia) in which D is xe2x80x94C(xe2x95x90O)xe2x80x94C(R21)(R22)xe2x80x94, can be prepared by the following reaction step: 
(In the formulae, R1, R2, R3, R4, R5a, R21, and R22 each has the same meaning as defined above.)
Compound (Iad) can be obtained by treating Compound (Iaa-aa), which is Compound (Iaa-a) in which R19a is hydrogen, with an oxidizing agent in an inert solvent containing water at the temperature between 0xc2x0 C. and the boiling point of the employed solvent for 5 minutes to 72 hours.
Examples of the oxidizing agent are manganese dioxide, potassium permanganate, pyridinium chlorochromate (PCC), and pyridinium dichromate (PDC).
Examples of the inert solvent are THF, dioxane, diethyl ether, ethylene glycol, triethylene glycol, glyme, diglyme, acetone, methyl vinyl ketone, dichloromethane, chloroform, benzene, toluene, DMF, and DMSO.
Process 1-5:
Compound (Iad) can also be prepared according to the following reaction step: 
(In the formulae, R26 is substituted or unsubstituted lower alkyl; and A, B, R1, R2, R3, R4, R5a, R21 and R22 each has the same meaning as defined above.)
Compound (Iad) can be obtained according to the method described in Process 1-1 in which Compound (Iaa-a) is obtained from Compound (II) and Compound (III), using Compound (IIa), which is a starting Compound (II) in which R19a is substituted or unsubstituted lower alkoxy.
Process 1-6:
Compound (Iad) can also be prepared by the following reaction step: 
(In the formulae, A, B, R1, R2, R3, R4, R5a, R21, and R22 each has the same meaning as defined above.)
The starting Compound (VIII) can be obtained according to the methods described in Reference Examples or similar methods thereto.
Compound (Iad) can be obtained by reacting Compound (VIII) with Compound (IX) in the presence of an acid catalyst in an inert solvent at the temperature between xe2x88x92100xc2x0 C. and the boiling point of the employed solvent for 5 minutes to 30 hours.
Examples of the acid catalyst are boron trifluoride, aluminium chloride, stannic chloride, titanium tetrachloride, zinc chloride, and ferric chloride.
Examples of the inert solvent are THF, dioxane, diethyl ether, glyme, diglyme, dichloromethane, 1,2,-dichloroethane, chloroform, benzene, nitrobenzene, and toluene.
Process 1-7:
Compound (Iae), which is Compound (Ia) in which D is xe2x80x94C(xe2x95x90O)xe2x80x94NR23xe2x80x94, can be prepared by the following reaction step: 
(In the formulae, A, B, R1, R2, R3, R4, R5a, and R23 each has the same meaning as defined above.)
The desired Compound (Iae) can be obtained by dehydrative condensation of Compound (IIb), which is a starting Compound (II) in which R19a is hydroxy, and Compound (VII). For the above condensation, numerous methods are known and applicable, as described in Jikken Kagaku Koza, 22, 137-172, the 4th edition (Nippon Kagakb-Kai, 1992). For example, Compound (IIb) is treated with one equivalent to a largely excess amount of thionyl chloride, phosphorus pentachloride, oxalyl chloride, or the like, if necessary in the presence of a catalytic amount to 20 equivalents of a base, in an inert solvent at the temperature between 0xc2x0 C. and the boiling point of the employed solvent for 0.1 to 48 hours to give a corresponding acid chloride. Then, the desired Compound (Iae) can be obtained by reacting the obtained acid chloride with 0.5 to 50 equivalents of Compound (VII), if necessary in the presence of 0.5 equivalent to a largely excess amount of a base, in an inert solvent at the temperature between 0xc2x0 C. and the boiling point of the employed solvent for 0.1 to 48 hours.
Examples of the base are those which are used in the manufacturing method for Compound (Iaa-a) described in Process 1-1.
Examples of the inert solvents are dichloromethane, chloroform, benzene, toluene, THF, dioxane, DMF, and DMSO.
Process 1-8:
Compound (Iaf), which is Compound (Ia) in which D is xe2x80x94C (xe2x95x90O)xe2x80x94Sxe2x80x94, can be prepared by the following reaction step: 
(In the formulae, A, B, R1, R2, R3, R4, and R5a each has the same meaning as defined above.)
Compound (Iaf) can be obtained according to the method described in Process 1-7 in which Compound (Iae) is obtained from Compound (IIc) and Compound (VII), using Compound (VI) instead of Compound (VII).
Process 1-9:
Compound (Iae-a), which is Compound (Iae) in which one of R1 and R11 (or R13) is xe2x80x94(CH2)nxe2x80x94COxe2x80x94G1 or xe2x80x94(CH2)mxe2x80x94COxe2x80x94G2, can be prepared by the following reaction steps: 
[In the formulae, Ga is OR6 (with the proviso that R6 is not hydrogen) or NR7R8 in the definition of G1 (or G2); R27 is a protective group of a carboxyl group; and A, B, R2, R3, R4, R5a, R23, n, and m each has the same meaning as defined above.]
A protective group for a carboxyl group is generally required to be deprotected selectively compared with an amide bond for converting a protected carboxyl group to a carboxyl group, and those which are described in the fifth chapter of Protective Group in Organic Synthesis (the second edition, Green and Watt, Jon Weary and Suns Incorporated, 1991) can be applied. Examples of these are esters of substituted or unsubstituted lower alkyl including methyl, ethyl, and tert-butyl, benzyl, allyl, and 2-(trimethylsilyl)ethyl.
The starting Compound (IIb-a) can be obtained according to the methods described in Reference Examples or similar methods thereto.
Compound (X) can be obtained according to the method described in Process 1-7, using Compound (IIb-a) and Compound (VII).
Compound (Iae-aa), which is Compound (Iae-a) in which G1 (or G2) is hydroxy, can be obtained by treating Compound (X) in the presence of a catalytic to largely excess amount of a base in an inert solvent containing water at the temperature between room temperature and the boiling point of the employed solvent for 0.1 to 48 hours.
Examples of the base are those which are used in the manufacturing method for Compound (Iaa-a) described in Process 1-1; and examples of the inert solvent are THF, dioxane, ethylene glycol, triethylene glycol, glyme, diglyme, methanol, ethanol, butanol, and isopropanol.
Compound (Iae-ab), which is Compound (Iae-a) in which G1 (or G2) is OR6 (with the proviso that R6 is not hydrogen) or NR7R8, can be obtained according to the method described in Process 1-7, using Compound (Iae-aa) and Compound Ga-H.
Process 1-10:
Compound (Iae-ac), which is Compound (Iae-a) in which G1 (or G2) is substituted or unsubstituted lower alkyl, cycloalkyl, polycycloalkyl, substituted or unsubstituted aryl, a substituted or unsubstituted aromatic heterocyclic group, or aralkyl, can be prepared by the following reaction step: 
[In the formulae, R27a is substituted or unsubstituted lower alkyl; Gb is substituted or unsubstituted lower alkyl, cycloalkyl, polycycloalkyl, substituted or unsubstituted aryl, a substituted or unsubstituted aromatic heterocyclic group, or aralkyl in the definition of G1 (or G2); and A, B, R2, R3, R4, R5a, R23, n, and m each has the same meaning as defined above.]
The substituted or unsubstituted lower alkyl in the definition of R27a has the same meaning as defined above.
Compound (Iae-ac) can be obtained by reacting Compound (Xa), which is Compound (X) in which R27 is substituted or unsubstituted lower alkyl, with an alkylating (arylating) agent (X) in an inert solvent at the temperature between xe2x88x92100xc2x0 C. and the boiling point of the employed solvent for 5 minutes to 30 hours.
Examples of the alkylating (arylating) agent are various kinds of alkyl- or arylmagnesium bromides, alkyl- or arylmagnesium chlorides, alkyl- or arylmagnesium iodides, and various kinds of alkyl or aryl lithium.
Examples of the inert solvent are THF, dioxane, diethyl ether, glyme, diglyme, methanol, ethanol, butanol, isopropanol, dichloromethane, chloroform, benzene, and toluene.
Process 1-11:
Compound (Iae-aca), which is Compound (Iae-ac) in which one of R1 and R11 (or R13) is xe2x80x94COxe2x80x94Gb, can also be prepared by the following reaction step: 
(In the formulae, A, B, R2, R3, R4, R5a, R23, and Gb each has the same meaning as defined above.)
Compound (Iae-aca) can be obtained according to the method described in Process 1-10 from Compound (Iae-b), which is Compound (Iae) in which R1 is cyano.
Process 1-12:
Compound (Iag), which is Compound (Ia) in which D is xe2x80x94C(xe2x95x90S)xe2x80x94Xxe2x80x94, can be prepared by the following reaction step: 
(In the formulae, A, B, R1, R2, R3, R4, R5a, and X each has the same meaning as defined above.)
Compound (Iag) can be obtained by treating Compound (Iad), Compound (Iae), or Compound (Iaf) with phosphorus pentasulfide or Lawesson""s reagent in an inert solvent at the temperature between room temperature and the boiling point of the employed solvent for 5 minutes to 72 hours.
Examples of inert solvent are pyridine, THF, dioxane, diethyl ether, ethylene glycol, triethylene glycol, glyme, diglyme, dichloromethane, chloroform, benzene, toluene, xylene, DMF, and DMSO.
Process 1-13:
Compound (Iah), which is Compound (Ia) in which D is xe2x80x94C(xe2x95x90NR20)xe2x80x94CR21R22xe2x80x94, can be prepared by the following reaction step: 
(In the formulae, R21a and R22a are groups other than lower alkanoyl, cycloalkanoyl, lower alkoxycarbonyl, and cyano in the definition of R21 and R22; and A, B, R1, R2, R3, R4, R5a, and R20 each has the same meaning as defined above.)
Compound (Iah-a), which is Compound (Iah) in which R21a and R22a are groups other than lower alkanoyl, cycloalkanoyl, lower alkoxycarbonyl, and cyano in the definition of R21 and R22, can be obtained by reacting Compound (Iad-a) with R20NH2 in the presence or absence of an acid catalyst in an inert solvent or without solvent at the temperature between room temperature and the boiling point of the employed solvent for 5 minutes to 48 hours.
Examples of the acid catalyst are p-toluene-sulfonic acid, methanesulfonic acid, hydrochloric acid, sulfuric acid, acetic acid, and trifluoroacetic acid.
Examples of the inert solvent are THF, dioxane, diethyl ether, ethylene glycol, triethylene glycol, glyme, diglyme, methanol, ethanol, isopropanol, tert-butanol, dichloromethane, chloroform, benzene, toluene, DMF, DMSO, and pyridine.
Process 1-14:
Compound (Iaxe2x80x2), which is Compound (I) in which D is (i) xe2x80x94C(R18)(R19)xe2x80x94Xxe2x80x94 and R5 is pyridine-N-oxide, can be prepared by the following reaction step: 
[In the formulae, Da is D in Compound (Iaa), (Iad), and (Iae) and A, B, R1, R2, R3, and R4 each has the same meaning as defined above.]
Compound (Iaxe2x80x2a), which is Compound (Iaxe2x80x2) in which D is D in Compound (Iaa), (lad), and (Iae), can be obtained by treating Compound (Iaa), (lad), or (Iae) with an oxidizing agent in an inert solvent at the temperature between room temperature and the boiling point of the employed solvent for 5 minutes to 72 hours.
Examples of inert solvent are dichloromethane, chloroform, benzene, toluene, xylene, DMF, DMSO, and acetic acid.
Examples of the oxidizing agent are peracetic acid, trifluoroperacetic acid, metachloroperbenzoic acid, hydrogen peroxide, benzoyl peroxide, tert-butyl hydroperoxide, and tert-amyl hydroperoxide.
Manufacturing method 2:
Compound (Ib), which is Compound (I) in which D is (ii) xe2x80x94C(R19a)xe2x95x90Yxe2x80x94, can be obtained by the following Processes 2-1 to 2-5.
Process 2-1:
Compound (Iba-a), which is Compound (Ib) in which Y is xe2x80x94CR24, R5 is substituted or unsubstituted aryl, or a substituted or unsubstituted aromatic heterocyclic group, R19a is a group other than hydroxy, substituted or unsubstituted lower alkoxy, and lower alkanoyloxy in the definition of R19a, and R24 and R19a are not combined to form a single bond, can be prepared by the following reaction steps: 
(In the formulae, R19ab is a group other than hydroxy, substituted or unsubstituted lower alkoxy, and lower alkanoyloxy in the definition as R19a, and R19a and R24 are not combined to form a single bond; and A, B, R1, R2, R3, R4, R5a, R19a, and R24 each has the same meaning as defined above.)
Compound (Iaa-aa), which is Compound (Iaa-a) in which R22 is hydrogen, can be obtained according to the method similar to the manufacturing method for Compound (Iaa-a) described in Process 1-1, using Compound (IIc) and Compound (IIIa), which is Compound (III) in which R22 is hydrogen. Compound (Iaa-aa) is directly converted to Compound (Iba) without isolation when R24 is lower alkanoyl, cycloalkanoyl, lower alkoxycarbonyl, or cyano.
Compound (Iba) can be obtained by treating Compound (Iaa-aa) in the presence an acid catalyst in an inert solvent at the temperature between room temperature and the boiling point of the employed solvent for 5 minutes to 48 hours.
Examples of the acid catalyst are p-toluene-sulfonic acid, methanesulfonic acid, hydrochloric acid, sulfuric acid, acetic acid, and trifluoroacetic acid.
Examples of the inert solvent are THF, dioxane, diethyl ether, ethylene glycol, triethylene glycol, glyme, diglyme, dichloromethane, chloroform, benzene, toluene, DMF, and DMSO.
Process 2-2:
Compound (Iba), which is Compound (Ib) in which Y is xe2x80x94CR24, R19a iS a group other than hydroxy, substituted or unsubstituted lower alkoyy, and lower alkanoyloxy in the definition of R19a, and R24 and R19a are not combined to form a single bond, can be prepared by the following reaction step: 
(In the formulae, A, B, R1, R2, R3, R4, R5, R19ab, and R24 each has the same meaning as defined above.)
The starting compound (XI) can be obtained according to the methods described in Reference Examples or similar methods thereto.
Compound (Iba) can be obtained by treating starting Compound (XI) with a base in an inert solvent at the temperature between xe2x88x92100xc2x0 C. and the boiling point of the employed solvent for 5 minutes to 10 hours, followed by reaction with Compound (XII) at the temperature between xe2x88x92100xc2x0 C. and the boiling point of the employed solvent for 5 minutes to 30 hours.
Examples of the base and the inert solvent are those used in the manufacturing method for Compound (Iaa-a) described in Process 1-1.
Process 2-3:
Compound (Ibb), which is Compound (Ib) in which Y is N, R19a is a group other than hydroxy, substituted or unsubstituted lower alkoxy, and lower alkanoyloxy in the definition of R19a, and R5 is substituted or unsubstituted aryl or a substituted or unsubstituted aromatic heterocyclic group, can be prepared by the following reaction step: 
(In the formulae, A, B, R1, R2, R3, R4, R5a, and R19ab each has the same meaning as defined above.)
Compound (Ibb) can be obtained by reacting Compound (IIe) with Compound (VIIa), which is Compound (VII) in which R23 is hydrogen, in the presence of an acid catalyst in an inert solvent or without solvent at the temperature between room temperature and the boiling point of the employed solvent for 5 minutes to 48 hours.
Examples of the acid catalyst are p-toluene-sulfonic acid, methanesulfonic acid, hydrochloric acid, sulfuric acid, acetic acid, and trifluoroacetic acid.
Examples of the inert solvent are THF, dioxane, diethyl ether, ethylene glycol, triethylene glycol, glyme, diglyme, methanol, ethanol, isopropanol, tert-butanol, dichloromethane, chloroform, benzene, toluene, DMF, and DMSO.
Process 2-4:
Compound (Ibc), which is Compound (Ib) in which Y is xe2x80x94CR24xe2x80x94CONHxe2x80x94, R19a is a group other than hydroxy, substituted or unsubstituted lower alkoxy, and lower alkanoyloxy in the definition of R19a, and R5 is substituted or unsubstituted lower aryl or a substituted or unsubstituted aromatic heterocyclic group, can be prepared by the following reaction steps: 
(In the formulae, R28 is lower alkyl. R24a is a group other than lower alkanoyl, cycloalkanoyl, lower alkoxycarbonyl, and cyano in the definition as R24; and A, B, R1, R2, R3, R4, R5a, and R19a each has the same meaning as defined above.)
The lower alkoxy in the definition of R28 has the same meaning as defined above.
Compound (Iba-b), which is Compound (Iba) in which R5 is lower alkoxycarbonyl and R24 is a group other than lower alkanoyl, cycloalkanoyl, lower alkoxycarbonyl, and cyano, can be obtained according to the method similar to the manufacturing method for Compound (Iba-a) described in Process 2-1, using Compound (II) and Compound (XIII). Further, Compound (Iba-b) can be obtained by reacting Compound (II) with a corresponding diester of phosphorous acid treated with a base in an inert solvent at the temperature between xe2x88x92100xc2x0 C. and the boiling point of the employed solvent for 5 minutes to 48 hours.
Examples of the inert solvent are THF, dioxane, diethyl ether, ethylene glycol, triethylene glycol, glyme, diglyme, methanol, ethanol, butanol, isopropanol, dichloromethane, chloroform, benzene, toluene, DMF, and DMSO.
Examples of the base are sodium hydroxide, potassium hydroxide, sodium methoxide, potassium ethoxide, sodium hydride, potassium hydride, butyl lithium, LDA, potassium tert-butoxide, triethylamine, diisopropyl-ethylamine, tributylamine, dicyclohexylmethylamine, N-methylmorphorine, N-methylpiperidine, DBU, and DBN.
Compound (Ibc-a), which is Compound (Ibc) in which R24 is a group other than lower alkanoyl, cycloalkanoyl, lower alkoxycarbonyl, and cyano, can be obtained according to the method described in Process 1-9 in which Compound (Iae-ab) is obtained from Compound (X), using Compound (Iba-b) and Compound (VIIa).
Process 2-5:
Compound (Ibd), which is Compound (Ib) in which Y is xe2x80x94CR24, R24 and R19a are combined to form a single bond, and R5 is substituted or unsubstituted aryl, or a substituted or unsubstituted aromatic heterocyclic group, can be prepared by the following reaction steps: 
(In the formulae, A, B, R1, R2, R3, R4, and R5a each has the same meaning as defined above.)
Compound (XIV) can be obtained by treating Compound (Iba-aa), which is Compound (Iba-a) in which R19a and R24 are both hydrogen, with a brominating agent in an inert solvent at the temperature between xe2x88x92100xc2x0 C. and the boiling point of the employed solvent for 5 minutes to 10 hours.
Examples of the inert solvent are THF, dioxane, diethyl ether, ethylene glycol, triethylene glycol, glyme, diglyme, methanol, ethanol, isopropanol, tert-butanol, dichloromethane, chloroform, benzene, toluene, DMF, and DMSO.
Examples of the brominating agent are bromine, tetrabutylammonium tribromide, tetramethylammonium tribromide, pyridinium tribromide, NBS, and copper bromide.
Compound (Ibd) can be obtained by treating Compound (XIV) with a base in an inert solvent at the temperature between xe2x88x92100xc2x0 C. and the boiling point of the employed solvent for 5 minutes to 10 hours.
Examples of the inert solvent are THF, dioxane, diethyl ether, ethylene glycol, triethylene glycol, glyme, diglyme, methanol, ethanol, isopropanol, tert-butanol, dichloromethane, chloroform, benzene, toluene, DMF, and DMSO.
Examples of the base are potassium hydroxide, sodium ethoxide, sodium methoxide, potassium tert-butoxide, and sodium amide.
Manufacturing method 3:
Compound (Ic), which is Compound (I) in which D is (iii) a bond, and R5 is substituted or unsubstituted aryl, or a substituted or unsubstituted aromatic heterocyclic group, can be obtained by the following process: 
(In the formulae, L1 and L2 independently represent iodine, bromine, or chlorine; and A, B, R1, R2, R3, R4, and R5a each has the same meaning as defined above.)
Examples of the metal halide are alkyltin halides such as tributyltin chloride and trimethyltin chloride, and zinc halides such as zinc chloride, zinc bromide, and zinc iodide; and examples of the boron compound are trimethoxy boron, phenylboric acid, and boric acid.
Compound (Ic) can be obtained by treating Compound (IIf) with a base in an inert solvent. at the temperature between xe2x88x92100xc2x0 C. and room temperature for 5 minutes to 10 hours, followed by reaction with a metal halide or a boron compound at the temperature between xe2x88x92100xc2x0 C. and the boiling point of the employed solvent for 5 minutes to 30 hours, and then reacting the obtained product with Compound (xv) in the presence of a catalytic to largely excess amount of a palladium complex in an inert solvent at the temperature between room temperature and the boiling point of the employed solvent for 5 minutes to 30 hours. Moreover, if necessary, a salt such as lithium chloride, or an oxidizing agent such as silver oxide may be added in case of the latter reaction.
Examples of the palladium complex are tetrakis(triphenylphosphine)palladium, bis(triphenyl-phosphine)palladium chloride, bis(acetonitrile)palladium chloride, and palladium acetate.
Examples of the base are sodium hydroxide, potassium hydroxide, sodium methoxide, potassium ethoxide, sodium hydride, potassium hydride, butyl lithium, LDA, potassium tert-butoxide, triethylamine, diisopropyl-ethylamine, tributylamine, dicyclohexylmethylamine, N-methylmorphorine, N-metylpiperidine, DBU, and DBN.
Examples of the inert solvent employed in the treatment with a base followed by reaction with a metal halide or a boron compound are THF, dioxane, diethyl ether, ethylene glycol, triethylene glycol, glyme, diglyme, methanol, ethanol, butanol, isopropanol, dichloromethane, chloroform, benzene, toluene, DMF and DMSO.
Examples of the inert solvent employed in the reaction with Compound (XV) ire THF, dioxane, diethyl ether, dichloromethane, chloroform, benzene, toluene, dimethylacetamide (DMA), DMF, and DMSO.
The intermediates and the desired compounds in the processes described above can be isolated and purified by purification methods conventionally used in organic synthetic chemistry, for example, filtration, extraction, washing, drying, concentration, recrystallization, and various kinds of chromatography. The intermediates may also be subjected to the subsequent reaction without isolation.
Compounds (I) can exist in the form of stereoisomers such as geometrical isomers and optical isomers, and the present invention covers all isomers including these isomers and mixtures thereof.
In the case where a salt of Compound (I) is desired and it is produced in the form of the desired salt, it can be subjected to purification as such. In the case where Compound (I) is produced in the free form and its salt is desired, Compound (I) is dissolved or suspended in a suitable solvent, followed by addition of an acid or a base to form a salt, which may be isolated and purified.
Compounds (I) and pharmaceutically acceptable salts thereof may be in the form of adducts with water or various solvents, which are also within the scope of the present invention.
Examples of Compound (I) obtained in the present invention are shown in Tables 1 to 20.
The pharmacological activities of the representative Compounds (I) are described in more detail by Test Examples.
cAMP-specific phosphodiesterase (PDE IV) was purified from a dog tracheal smooth muscle according to the method of Torphy et al. [Molecular Pharmacol., 37, 206-214 (1990)]. The PDE activity was measured by the following two steps according to the method of Kincaid and Manganiello et al. [Method in Enzymology (J. D. Corbin and R. A. Jonson, Eds.), 199, 457-470 (1988)]. Using [3]cAMP (at a final concentration of 1 xcexcM) as a substrate, the reaction was carried out in a standard mixture containing N,N-bis(2-hydroxyethyl)-2-aminoethanesulfonic acid (50 mM, pH=7.2), MgCl2 (1 mM), and soybean trypsin inhibitor (0.1 mg/ml). The reaction was initiated by adding the enzyme, followed by incubation at 30xc2x0 C. for 10 to 30 minutes. After stopping the reaction with hydrochloric acid, the generated 5xe2x80x2-cAMP was completely converted to adenosine by 5xe2x80x2-nucleotidase.
The resultant was subjected to chromatography on DEAE-Sephadex A-25, and radio activity of the eluted [3H] adenosine was counted using a scintillation counter. Each of the test drugs was dissolved in DMSO (final concentration 1.7%) and then added to the mixture.
The results are shown in Table 21.
The CDNA encoding phosphodiesterase 4A was isolated from human testis CDNA library. It predicts a truncated protein lacking 223 amino acids at the N-terminus from the sequence previously reported by Bolger, G., et.al. [Mol. Cell. Biol. 13, 6558-6571 (1993)]. The E. coli expression plasmid expressing this recombinant protein was constructed, and the expressed protein was partially purified. PDE activity was measured by the two-step procedure as previously described by Kincaid, R., L. and Manganiello, V., C. [Method. Enzymol. 159, 457-470 (1988)]. The reaction mixture contained (final concentrations) 50 mmol/L N, N-bis(2-hydroxyethyl)-2-aminoethansulfonic acid (pH 7.2), 1 mmol/L MgCl2, 0.1 mg/mL Soybean trypsin inhibitor, and 1 mmol/L [3H]cAMP. The reactions were initiated by addition of the enzymes, incubated at 30xc2x0 C. for 10 to 30 minutes, depending on the activity of the enzymes, and terminated by addition of hydrochloric acid. The product, [3H]5xe2x80x2-AMP was completely converted by snake venom 5xe2x80x2-nucleotidase, and resulted [3H]adenosine was separeted by DEAE-Sephadex A-25 column. Radioacitivity of eluted adenosine was measured using scintillation counter. All compounds tested were dissolved in DMSO at several different concentrations, and added to reaction mixtures at 1.7 v/v %.
In this study, PDE4A activity was reduced by more than 50% by addition of 10 mmol/L of the compounds tested.
The results are shown in Table 22.
For passive sensitization, rabbit anti-ovalbumin serum prepared by the method of Kohda et al. [Nichiyakurishi, 66, 237 (1970)] was peritoneally administered to male Hartley guinea pigs weighing 350 to 500 g, and 24 hours later the tracheae thereof were removed to be used for the experiment. Zig-zag strips were prepared from the tracheae in accordance with the method of Emmerson and Mackay [J. Pharm. Pharmacol., 31, 798 (1979)], and they were suspended in a Krebs-Henseleit solution with aeration of a mixture of 95% oxygen and 5% carbon dioxide at 37xc2x0 C. After stabilizing for approximately one hour, ovalbumin, as the antigen, was added to the mixture (at a final concentration of 1 xcexcm/ml), and the constriction of the muscle was recorded by a recorder (TYPE 3066; Yokokawa Hokushin Denki) via an isotonic transducer (TD-112S; Nippon Koden). A test compound was cumulatively added to the mixture after the constriction had reached the plateau, and the relaxation ratio was determined. The concentration (IC50) causing 50% relaxation was calculated by linear regression analysis. The IC50 value of Compound 68 of the present invention was 1.6 xcexcM.
This test was carried out by a modified Konzett and Rossler method. Under anesthesia with urethane (1.2 g/kg, ip), male Hartley guinea pigs (body weight: 500 to 600 g) were fixed on plates by strings. After undertaking a tracheotomy, cannulae were inserted to the tracheae, right carotid arteries, and left cervical veins. The spontaneous respiration of the guinea pigs was stopped by the administration of gallamie (10 mg/kg) from the left cervical veins via the cannulae. The cannulae inserted into the tracheae were connected to a bronchospasm transducer (Ugo Basile) and a respirator (TB-101, Takashima-shoten, 60 to 70 strokes/minutes, output: 5 cc) and the air overflow volume was recorded by a polygraph (RM-45, Nippon Koden) to measure the amount of bronchoconstriction. For measuring blood pressure, the cannulae inserted in the right carotid arteries were connected to a blood-pressure transducer. Constant bronchoconstriction occurred when histamine (10 xcexcg/kg, iv) was administered at 3 minutes intervals, and the induced bronchoconstriction was used as the control. A test compound was intravenously administered, and one minute later histamine (10 xcexcg/kg, iv) was administered. The test compound was cumulatively administered at 5 minutes intervals, and the bronchoconstriction in control and that after the administration of the test compound was compared.
In this test, the ID50 value (50% inhibitory dose) of Compound 68 was 0.076 mg/kg in the case of intravenous administration.
For passive sensitization, 1 ml of rabbit anti-ovalbumine serum was peritoneally administered to male Hartley guinea pigs, and 16 to 24 hours later, ovalbumine was intravenously administered as the antigen. The induced anaphylactic bronchoconstriction was measured by the modified Konzett and Rossler method. Each of the tracheal cannulae was completely closed at the end of the measurement and the measured constriction was defined as the maximum constriction. Changes in the constriction were measured as percentage in the maximum constriction. The area under the curve (AUC) indicating the strength of the response was calculated by an image analyzer (MCID system, Imaging Research Company). The test compound was orally administered one hour before the antigen administration, and the ID50 value of each drug was calculated from the AUC suppression ratio by linear regression analysis.
In this test, the ID50 value (50% inhibitory dose) of Compound 100 was 0.53 mg/kg by oral administration.
Lipopolysaccharide (LPS, DIFCO Laboratories) was dissolved in physiological saline to make a final concentration of 0.2 mg/ml. The resulting solution was administered intravenously to the tail of Balb/c male mice (7-week-old) (Charls River Japan Co.) at 200 xcexcl per 20 g body weight of 5 to 6 mice/group. One hour after administration, blood was drawn from a fundus oculi vein of each mouse to obtain serum. Each sample of the test compound was dissolved or suspended in a 0.5% methyl cellulose solution to make a final concentration of 1 mg/ml, and then, administered orally to the mice at 200 xcexcl per 20 g body weight 90 min. before the administration of LPS. The concentration of TNF a in serum was measured by enzyme-linked immunosorbent assay (ELISA method) as follows: 4 mg/ml anti-mouse TNF a monoclonal antibody (Pharmingen Inc.) diluted with a phosphate buffer solution (PBS) was added to a 96-well microtiter plate (Nalge Nunc International immuno-plate  less than MaxiSorp=) at 50 ml/well; allowed to stand at 4xc2x0 C. for 12 hours for coating; mixed with 200 ml/well of a phosphate buffer solution containing 1% bovine serum albumin (BSA) (1% BSA-PBS); allowed to stand at room temperature for 1 hour to block the non-specific binding; washed with phosphate buffer solution; mixed with 100 ml/well of the subject serum diluted two-fold with 1% BSA-PBS; and allowed to stand at room temperature for 2 hours. Furthermore, recombinant mouse TNF xcex1 (Genzyme Corp.) diluted with 1% BSA-PBS was similarly treated and used as a standard substance. These plates were washed three times with PBS (0.05% Tween-PBS) containing 0.05% polyoxyethylenesorbitan monolaurate (Tween 20, Wako Pure Chemical Industries, Ltd.), mixed with 50 ml/well of biotin-labelled anti-mouse TNF xcex1 monoclonal antibody (Method A: Pharmingen Inc.; Method B: Genzyme Corp) diluted with 1% BSA-PBS to make a concentration of 1 mg/ml, allowed to stand at room temperature for 1 hour, washed three times with 0.05% Tween-PBS, mixed with 100 ml/well of horseradish peroxidase avidin D (Vector Laboratories Inc.) diluted four-thousand-fold with 1% BSA-PBS, and allowed to stand at room temperature for 30 min. Finally, these plates were washed three times with 0.05% Tween-PBS, and mixed with 100 ml/well of 3,3xe2x80x2,5,5xe2x80x2-tetramethylbenzidine. After color development, the reaction was stopped by adding 100 ml/well of 10% sulfuric acid solution, and then, the absorbance at 450 nm was measured. The concentration of TNF xcex1 in serum was calculated from a calibration curve.
The rate of suppression of each test compound on TNF xcex1 production was obtained from the following formula:
Suppression rate=(Axe2x88x92B)/A,
wherein A is the TNF xcex1 concentration of the control group and B is the TNF xcex1 concentration of the experimental group.
In the above formula, the TNF xcex1 concentration of the control group is defined as the value obtained in the absence of the test compound (0.5% methyl cellulose solution alone).
Employed as the reference compounds were 7-methoxy-4-[1-oxo-2-(4-pyridyl)ethyl]-spiro[2,3-dihydrobenzofuran-2,1xe2x80x2-cyclopentane] hydrochloride (disclosed in Example 100 of Japanese Patent Laid-Open No. 8-836624 and hereinafter referred to as Compound RA) having the formula (RA) and 2-benzoyl-4-(3,5-dichloro-4-pyridyl)aminocarbonyl)-7-methoxybenzofuran (disclosed in Example 35 of Japanese Patent Laid-Open No. 8-534708 and hereinafter referred to as Compound RB) having the formula (RB): 
Table 23 shows the results.
Five to fifteen male Sunkus murinus per group weighing approximately 60 g were used for the test. According to the method of Matsumoto, et. al. [Japan J. Pharmacol., 48, 303 (1988)], Sunkus murinus were placed separately into metal wire cages (width 15 cmxc3x97length 21 cmxc3x97height 15 cm). Each sample of the test compound was suspened in a 0.5% Tween 80 physiological saline solution and administered intraperitoneally (i.p.) at a dose of 10 ml/kg. The animals were observed for 1 hour after administration of the test compound to count the vomiting number. In the group that was administered the test-compound, the results are represented as the number of vomiting animals/the number of experimental animals. Compound RA was employed as a reference compound. Table 24 shows the results.
As is shown in Tables 23 and 24, the suppression effect of Compounds 201 to 205 of the present invention on the production of TNF xcex1, which activates the inflammatory leukocytes, is stronger than that of Compound RB. In addition, Compounds of the present invention are superior to Compound RA in that they reduce vomiting which is a general side effect of PDE IV inhibitor.
The Howell et al""s method (Pulmonary Pharmacology, 8, 83-59 (1995)) was partly modified and used for the active sensitization and the antigen exposure.
Oval albumin (OA) (1 mg) and aluminium hydroxide (200 mg) were subcutaneously injected into male Brown-Norway rats (6 week-age, Nippon Charles River), to which were intra abdominally administered dead cells of Bordetella pertussis for the active sensitization of the rats. After 14 days, the rats were put into a plastic chamber (30xc3x9750xc3x9730 cm), and left to inspire a 1% (w/v) OA solution for 10 minutes for antigen induction. For the inspiration, used was an ultrasonic nebulizer (NE-U12, by Omron, Tokyo).
The test compound was suspended in 0.5% methyl cellulose, and orally administered (p.o.) to the rats one hour prior to the antigen challenge. The group of the rats to which 0.5% methyl cellulose was administered and which were left to inspire OA was referred to as OA Group, while the group of the rats which were left to inspire a physiological saline solution in place of OA was referred to as Saline Group.
After 24 hours from the antigen induction, bronchoalveolar lavage (BAL) was performed. Briefly, the rats were anesthetized with pentobarbital (100 mg/kg, i.p.), to which was applied a physiological saline solution (37xc2x0 C., 4 ml) via a tracheal cannula, using a disposable syringe (5 ml Terumo Syringe, by Terumo, Tokyo), and recovered after about 15 seconds. This operation was repeated two times to obtain bronchoalveolar lavage fluid (BALF). This BALF was centrifuged at 950 rpm for 10 minutes at 4xc2x0 C., and the precipitated cells were suspended in a physiological saline solution (1 ml). Then, the number of all leukocytes existing in the resulting suspension was counted, using an automatic leukocyte counter (Celltac xcex1 MEK-6158, by Nippon Koden, Tokyo). On the other hand, smears of the cells were prepared, using Cytospin 3 (by Shandon, Pittsburgh, USA), and stained with Wright-Giemsa. Those cells of 500 were observed with an optical microscope to count eosinophils (Eos), neutrophiles (Neu), lymphocytes (Lym), macrophages (Mac) and other cells (Oth), from which were obtained the proportions of those cells. The data were multiplied by the number of all leukocytes to obtain the actual numbers of those cells in BALF.
In this experiment, Compound 216 exhibited 100% inhibiting activity against eosinophils and 92% inhibiting activity against neutrophils, at a dose of 30 mg/kg.
Although Compound (I) or pharmaceutically acceptable salts thereof may be administered as they are, it is usually desirable to provide them in the form of various pharmaceutical preparations. Such pharmaceutical preparations may be used for animals and human beings.
The pharmaceutical preparations in accordance with the present invention may contain Compound (I) or a pharmaceutically acceptable salt thereof, as an active ingredient, either solely or as a mixture with other therapeutically effective components. The pharmaceutical preparations may be prepared by any means which are well known in the technical field of pharmaceutics after mixing the active ingredient with one or more pharmaceutically acceptable carriers.
It is desired to use the administration route which is the most effective in therapy such as oral route or parenteral route which includes intrabuccal, intratracheal, intrarectal, subcutaneous, intramuscular, and intravenous administrations.
Examples of the dosage form are nebulae, capsules, tablets, granules, syrups, emulsions, suppositories, injections, ointments, and tapes.
Liquid preparations suitable for oral administration such as emulsions and syrups can be prepared using water; sugars such as sucrose, sorbitol, and fructose; glycols such as polyethylene glycol and propylene glycol; oils such as sesame oil, olive oil, and soybean oil; preservatives such as p-hydroxybenzoate; flavors such as strawberry and peppermint; and the like. Capsules, tablets, powders, granules, and the like can be prepared using excipients such as lactose, glucose, sucrose, and mannitol; disintegrators such as starch and sodium alginate; lubricants such as magnesium stearate and talc; binders such as polyvinyl alcohol, hydroxypropyl cellulose, and gelatin; surfactants such as fatty acid esters; plasticizers such as glycerin; and the like.
Preparations suitable for parenteral administration comprise sterilized aqueous preparations of the active compound which are preferably isotonic to the blood of the patient. For example, a solution for injection is prepared using a carrier such as a salt solution, a glucose solution, or a mixture of a salt solution and a glucose solution. Preparations for intrarectal administration are prepared using a carrier such as cacao fat, hydrogenated fat, or a hydrogenated carboxylic acid, and provided as suppositories. Nebulae are prepared using an active compound per se or with carriers which can disperse the active compound as fine particles to facilitate absorption without stimulating oral or respiratory mucosa. Practical examples of the carrier are lactose and glycerin. Preparations such as aerosols and dry powders can be used depending upon the properties of the active compound and the employed carriers.
These parenteral preparations may also contain one or more auxiliary components selected from diluents, flavors, preservatives, excipients, disintegrators, lubricants, binders, surfactants, and plasticizers, all of which are mentioned in the above oral preparations.
The effective dose and the administration schedule of Compounds (I) or pharmaceutically acceptable salts thereof may vary depending upon the administration route, age and body weight of a patient, and the type or degree of the disease to be treated, but usually, in the case of oral administration, the effective compound is administered in a dose of 0.01 mg to 1 g, preferably, 0.05 to 50 mg/person/day at one time or in several parts. In the case of parenteral administration such as intravenous injection, the effective compound is administered in a dose of 0.001 to 100 mg, preferably, 0.01 to 10 mg/person/day at one time or in several parts. These doses should, however, vary depending upon various conditions as given above.